Parkinson's disease is a progressive disorder of the central nervous system affecting over 1.5 million people in the United States. Parkinson's disease is caused by the degeneration of the pigmented neurons in the substantia nigra of the brain, resulting in decreased dopamine availability to the striatum. Clinically, the disease is characterized by a decrease in spontaneous movements, gait difficulty, postural instability, rigidity and tremor.
The most common and effective drug for treatment of PD is levodopa, either administered alone or in combination with a peripheral dopa decarboxylase inhibitor such as carbidopa. After about 5 years of treatment, however, the majority of PD patients experience a “wearing-off” of drug effect, and often exhibit abnormal motor side effects (e.g., dyskinesias and dystonias) in response to the levodopa. These problems limit the long-term benefit that can be achieved with this drug.
Currently, the dose of levodopa can be reduced somewhat by adding dopamine agonists such as bromocriptine mesylate (Parlodel), pergolide mesylate (Permax), pramipexole (Mirapex), or ropinirole hydrochloride (Requip), however, these drugs have no effect on the duration of anti-parkinson efficacy of levodopa. Enzyme inhibitors such as a catechol-O-methyl transferase inhibitors (tolcapone or entacapone) or monoamine oxidase B inhibitors (selegiline) may extend the duration of levodopa's therapeutic effect. However, dopamine agonists and enzyme inhibitors directly manipulate dopamine neurochemistry. Side effects related to excess dopaminergic neurotransmission, such as dyskinesias and psychoses, are thus often produced when these drugs are used in conjunction with levodopa to treat PD. Also, neither the dopamine agonists nor the enzyme inhibitors have significant anti-Parkinson effects of their own.
Up to 80% of PD patients on levodopa therapy develop levodopa-induced, choreiform dyskinesias after 2–5 years of levodopa use. When levodopa-induced dyskinesias first emerge, they are mainly the peak-dose type; i.e., the dyskinesias are most prominent in PD patients when plasma levodopa levels are high. After chronic levodopa treatment, dyskinesias can appear at the beginning and again at the end of the period during which an individual levodopa has a beneficial effect. In more advanced PD, dyskinesias can be present throughout the duration of a single oral dose of levodopa, often masking any beneficial effects of the drug.
Functional models of levodopa-induced dyskinesias suggest that there is enhanced excitation in the striatum, which may be linked to the spontaneous release of glutamate after dopamine denervation. Drugs that act directly to antagonize glutamate receptors would likely not be useful in treating levodopa-induced dyskinesias, since there is little evidence of gross alterations in the levels or synthesis of any glutamate receptor subtype in parkinsonian brains. Thus, the abnormal glutamate-mediated influences that underlie levodopa-induced dyskinesias are most likely caused by altered glutamate neurotransmission.
Drugs such as amantadine or riluzole have recently been proposed as anti-dyskinesia treatments to be used in conjunction with levodopa. Some of these drugs reduce the efficacy of levodopa while minimizing dyskinesias, but none have enhanced the therapeutic effect of levodopa. Moreover, amantadine as well as other drugs that indiscriminately block glutamate receptors can cause confusion, hallucinations, depression, nightmares, and blurred vision, and the anti-dyskinetic effect wears off after a few weeks of treatment.
Chronic levodopa therapy can also cause other sides effects such as dystonias (e.g., sustained muscle contractions resulting in abnormal postures). The type and pattern of levodopa side effects can differ from patient to patient. It is not known why levodopa causes different side effects in different patients; however, dystonias and dyskinesias are believed to be caused by dysfunctions in different neural systems.
The emergence of levodopa-induced side effects presents a dilemma for the management of PD patients. For example, a decrease in the levodopa dose may relieve the side effects, but is achieved at the expense of increasing PD symptoms. In pharmacological terms, the therapeutic index of levodopa lessens over time, because the incidence of toxic side-effects increases for a given levodopa dose over the course of treatment.
Altered N-methyl D-aspartate (“NMDA”) receptor transmission may also be involved in abnormal neural activity in basal ganglia circuits following dopamine depletion in PD patients. Receptor binding studies have shown that NMDA receptors in dopamine-depleted striata have increased neuron “activatability” in the presence of glutamate and glycine. Also, the animal experimental literature reports that antagonists of excitatory NMDA receptors may exert anti-parkinsonian effects.
However, the clinical usefulness of specific NMDA antagonists in treating PD is limited, because such drugs produce severe, debilitating side effects. Likewise, although drugs that block specific NMDA receptor subtypes may have some anti-parkinson properties and may reduce dyskinesias, it is unclear which NMDA subtypes need to be blocked to effectively treat PD.
Drugs that can simultaneously act as both agonists and antagonists and are called “partial agonists.” The agonist or antagonist properties of such drugs are often dependent on their concentration within the brain relative to endogenous neurotransmitter levels. In parts of the brain where endogenous neurotransmitter levels are relatively low, a partial agonist can increase receptor stimulation. In regions where neurotransmitter levels are relatively high, partial agonists can act as antagonists and reduce receptor stimulation.
Glycine is a coagonist of the NMDA receptor with respect to activation of both the glutamate and glycine sites required for channel opening. Drugs like D-cycloserine or 1-aminocyclopropanecarboxylic acid (ACPC) are partial agonists for the glycine binding site of the NMDA receptor. These drugs, also called “partial glycine agonists,” can act as agonists or antagonists at the NMDA receptor glycine binding site, depending on their concentration in the brain relative to endogenous glycine. Generally, partial glycine agonists act as antagonists at high concentrations in the brain relative to glycine, without directly blocking the NMDA receptor.
The partial glycine agonists have no affinity for neurotransmitter uptake sites, and, unlike NMDA channel blockers, do not produce motor incoordination or ataxia. Thus, partial glycine agonists acting as antagonists have a safer side effect profile compared to drugs that act directly on NMDA, adrenergic, histaminergic, cholinergic or glutamatergic receptors.
There is a need for a drug which increases the therapeutic efficacy of levodopa in PD patients without producing toxic side-effects related to excess dopamine neurotransmission, or the direct inhibition of NMDA and other neuroreceptors. Ideally, the treatment would also reduce the severity and frequency of levodopa-induced dyskinesias in PD patients during the course of levodopa therapy.